Submissions for variant NM_003036.4(SKI):c.100G>A (p.Gly34Ser)

dbSNP: rs387907306

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200686	SCV000250672	pathogenic	not provided	2014-12-11	criteria provided, single submitter	clinical testing	p.Gly34Ser (GGC>AGC): c.100 G>A in exon 1 of the SKI gene (NM_003036.3) The G34S mutation in the SKI gene has been reported in three individuals with clinical diagnoses of SGS (Doyle et al., 2012; Carmignac et al., 2012, Schepers et al., 2014). The Gly34 residue appears to be a recurrent mutation hotspot in the R-SMAD binding domain of the SKI gene, as different mutations impacting this amino acid (G34D, G34C, G34V) have been reported (Doyle et al., 2012; Carmignac et al., 2012, Schepers et al., 2014). Mutations in nearby residues (S31L, L32V, L32P, P35S, P35Q) have also been reported in association with SGS, further supporting the functional importance of this region of the protein. G34S results in a non-conservative amino acid substitution of Glycine at a position that is conserved, when present, across species. This variant was found in TAADV2-1,SKI
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000030819	SCV000266520	pathogenic	Shprintzen-Goldberg syndrome		criteria provided, single submitter	research
Ambry Genetics	RCV000624509	SCV000741801	pathogenic	Inborn genetic diseases	2016-09-15	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000030819	SCV000803523	likely pathogenic	Shprintzen-Goldberg syndrome	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Shprintzen-Goldberg craniosynostosis syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24736733). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:23023332,23103230,24736733).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030819	SCV002511658	pathogenic	Shprintzen-Goldberg syndrome	2022-04-26	criteria provided, single submitter	clinical testing	Variant summary: SKI c.100G>A (p.Gly34Ser) results in a non-conservative amino acid change located in the R-SMAD domain (Carmignac_2012) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 95400 control chromosomes. c.100G>A has been reported in the literature in individuals affected with Shprintzen-Goldberg Syndrome (example, Doyle_2012, Carmignac_2012, Au_2014, Schepers_2015, Nayak_2021). Mutations in exon 1 of SKI have recently been identified as being responsible for approximately 90% of reported individuals diagnosed clinically with Shprintzen-Goldberg syndrome (Au_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000030819	SCV000053494	pathogenic	Shprintzen-Goldberg syndrome	2015-02-01	no assertion criteria provided	literature only
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000030819	SCV001427382	pathogenic	Shprintzen-Goldberg syndrome	2019-01-01	no assertion criteria provided	clinical testing